The long-term goal of our research program is to provide a mechanistic understanding of the functional role played by cell adhesive interactions in retinal growth and development and the contribution aberrant cell adhesive interactions make to the pathogenesis of retinal diseases. It is highly likely that retinal pathologies involving alterations of retinal cell growth and phenotype, including proliferative disorders such as retinoblastoma and proliferative vitreoretinopathy, involve inappropriate expression or function of cell adhesive mechanisms that normally contribute to retinal homeostasis in the adult. The experiments described in this application are specifically designed to test the central hypothesis that the coordinated regulation of retinal cadherin cell adhesion molecules is critical to the normal growth and differentiation of retinal cells. During the prior project period, we have provided evidence in support of this hypothesis and have further identified potential mechanisms by which this regulation may be controlled. In order to critically test this hypothesis, the experiments described in this application are directed at addressing three specific aims, utilizing a combination of cell biological, biochemical and molecular genetic approaches. Specific aim 1. To test the hypothesis that N-cadherin and R-cadherin respectively regulate early versus late steps in the differentiation of retinal pigment epithelial cells. Specific aim 2. To test the hypothesis that coordinate regulation of N-cadherin and R-cadherin expression during retinal differentiation is mediated by a combination of genetic and epigenetic mechanisms. Specific aim 3. To test the hypothesis that N-cadherin and R-cadherin mediate distinct downstream effects on cytoskeletal organization, cell growth and differentiation in a model of primitive retinal cells using retinoblastoma cell lines. These hypothesis-driven studies will provide important new information regarding the role of cadherin cell adhesion molecules in the regulation of neural retinal and retinal pigment epithelial cell growth and differentiation.